1. Field of the Invention
The invention generally relates to inhibition of exocytosis by inhibiting the proteins that regulate exocytosis. In particular, the invention provides fusion peptides that cross cell membranes and inhibit N-ethylmaleimide Sensitive Factor (NSF), thus blocking exocytosis.
2. Background of the Invention
Exocytosis is a necessary and beneficial cellular process. However, disorders of exocytosis can result in severe and debilitating pathological conditions. These diseases include inflammatory and thrombotic disorders, including unstable angina, myocardial infarction, transient ischemic attack, and stroke. Thus, the ability to regulate exocytosis is a desideratum in the medical field.
One major pathway of exocytosis that is related to inflammation is exocytosis of Weibel-Palade bodies. Weibel-Palade bodies are endothelial granules, the contents of which include von Willebrand factor (vWF), P-selectin, tissue plasminogen activator, and CD63, and are known to mediate vascular inflammation and thrombosis. As such, Weibel-Palade exocytosis is an attractive target for regulation via medical intervention.
U.S. Pat. No. 6,461,616 to Shone et al. (Oct. 8, 2002) discloses recombinant polypeptides with two domains. The first domain allows the polypeptide to be translocated into a target cell or increases the solubility of the polypeptide, and the second domain allows inhibition of vesicle or plasma-membrane associated proteins essential to exocytosis, thereby inhibiting exocytosis.
U.S. Pat. No. 6,506,399 (Jan. 14, 2003) to Donovan discloses biodegradable botulinum toxin implants containing a therapeutic element which, when present in the cytoplasm of a neuron, inhibits exocytosis of acetylcholine from the neuron.
U.S. Pat. No. 6,623,980 B1 to Fisher et al., (Sep. 23, 2003) describes novel exocytotic polypeptides Exo1 and Exo2, and the use of the polypeptides to identify compositions which mediate exocytotic polypeptide bioactivity.
U.S. Pat. No. 6,632,440 to Quinn et al. (Oct. 14, 2003) describes methods and compounds useful for treating disorders related to the hypersecretion of mucus by inhibiting exocytosis in mucus secreting cells, and/or inhibiting neurotransmitter release from neuronal cells controlling or directing mucus secretion.
U.S. Pat. Nos. 5,817,789 (Oct. 6, 1998) and 6,027,921 (Feb. 22, 2000) to Heartlin et al., describe chimeric proteins which include a first domain that is a ligand-binding domain of a first receptor, and a carrier domain that binds a cell surface receptor other than the first receptor. The chimeric protein is transported into the cell upon binding of the carrier domain to the cell surface receptor.
Given the meager amount of methodology in the field, there is an ongoing need to develop novel compositions and methods for regulating exocytosis in order to treat pathological conditions that result from disorders of exocytosis. In particular, the prior art has thus far failed to provide adequate means of regulating exocytosis of Weibel-Palade bodies, and thus for treating or preventing related disorders.